Myeloma is characterized by the accumulation of malignant plasma cells in the bone marrow and is accompanied by severe bone disease. Myeloma afflicts more than 14,000 people in the US each year; despite advances in treatment, myeloma remains incurable, highlighting the importance of developing novel interventions for this disease. We demonstrated the interdependence between myeloma bone disease and tumor progression. Therefore, we propose an innovative treatment paradigm based on creating an inhospitable bone marrow environment for myeloma through stimulating bone formation, increasing antitumor osteoblastic factors, and blocking activity of osteoclastic factors that promote myeloma. This therapeutic concept is supported by clinical observations and by our previous and preliminary studies demonstrating that osteoblasts inhibit myeloma growth and that osteoblast-activating agents induce bone formation while also reducing myeloma burden in vivo. Moreover, osteoblasts produce high levels of small-leucine-rich-proteoglycans (SLRPs), which are essential for proper bone remodeling and, notably, also inhibit some tumor types; our preliminary study revealed that SLRPs suppress myeloma growth. We also showed that osteoclasts support myeloma growth via physical contact, and we identified fibroblast activation factor (FAP) as a critical microenvironmental factor involved in this processes. Our overall hypothesis is that factors upregulated on osteoclasts in myelomatous bone promote myeloma cell survival and that bone-building factors produced by osteoblasts negate myeloma progression. We will exploit our unique in vivo and ex vivo systems for primary myeloma to study three Specific Aims. We will (Aim 1) determine the involvement of SLRPs in osteoblast-induced myeloma growth inhibition and unravel anti-myeloma molecular mechanisms of these proteoglycans ex vivo and in vivo. We will test the effect of blocking SLRPs on osteoblast-induced myeloma growth inhibition, unravel SLRPs molecular mechanisms, and test their anti-myeloma efficacy. We will (Aim 2) determine the effects of the potent osteoblast-activating factors, dickkopf-1 (DKK1) neutralizing antibody, parathyroid hormone (PTH) and bortezomib on myeloma bone disease and myeloma development and progression in primary myelomatous SCID-rab mice. We will (Aim 3) determine the role of FAP in myeloma pathogenesis and as a potential microenvironment-targeted therapy; using recombinant FAP, specific FAP inhibitors and short-interfering RNA approaches we will unravel direct and indirect effects of FAP on myeloma progression in vitro and in vivo. Work under this study will validate novel microenvironmental-targeted therapies associated with activation of osteoclasts and explore the use of bone-anabolic agents and SLRPs as effective and safe strategies to improve patients' quality of life and control myeloma. Project Narrative: Malignant myeloma cells manifest in the bone marrow and cause severe, painful bone disease. Our main goal is to create a hostile environment for tumor cells by controlling myeloma-induced bone destruction. Our study will increase knowledge of myeloma pathogenesis, which will help develop new approaches to treat myeloma bone disease and tumor progression simultaneously, improve patients' quality of life, and prevent myeloma development in individuals who are at risk for developing this incurable disease.